Mutations in SF3B1 lead to altered RNA splicing and contribute to CLL pathogenesis.
Chronic lymphocytic leukemia (CLL) is biologically and clinically heterogeneous, with some patients enjoying many years of treatment-free survival while others experience relentless disease progression. To better understand the molecular underpinnings of this heterogeneity, investigators performed massively parallel sequencing of paired tumor and germline DNA from 91 CLL patients. Acquired somatic mutations were identified by comparing whole genome and whole exome sequences from the tumor cell and normal DNA.
Recurring mutations were confirmed in four genes previously known to be associated with CLL: TP53, ATM, MYD88, and NOTCH1. Five additional genes with recurring mutations were also identified. The most common of these (found in 15% of cases) involved splicing factor 3b subunit 1 (SF3B1), a critical component in RNA splicing and processing. SF3B1 mutations strongly correlated with the presence of del(11q), ATM mutations, or both, as well as a short time to initial treatment. Investigations are under way to better understand the pathogenetic mechanisms associated with the generation of aberrant RNA transcripts.
Comment: This discovery of mutations in this key component of RNA processing parallels those previously identified in CLL regulatory microRNAs). Of note, SF3B1 mutations are also present in myelodysplastic syndromes, especially refractory anemia with ringed sideroblasts), and less commonly in solid tumors, indicating that these mutations might underlie the pathogenesis of disparate cancer types.
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